Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome.

Autor: Berg EL; MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA., Pride MC; MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA., Petkova SP; MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA., Lee RD; MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA., Copping NA; MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA., Shen Y; MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA., Adhikari A; MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA., Fenton TA; MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA., Pedersen LR; MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA., Noakes LS; Mouse Imaging Centre, Toronto Centre for Phenogenomics, The Hospital for Sick Children, Toronto, ON, Canada., Nieman BJ; Mouse Imaging Centre, Toronto Centre for Phenogenomics, The Hospital for Sick Children, Toronto, ON, Canada., Lerch JP; Wellcome Centre for Integrative Neuroimaging, The University of Oxford, Oxford, UK., Harris S; Department of Pediatrics and Neurology, Baylor College of Medicine, Houston, TX, USA., Born HA; Department of Pediatrics and Neurology, Baylor College of Medicine, Houston, TX, USA., Peters MM; Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA., Deng P; Stem Cell Program, Institute for Regenerative Cures, and Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, USA., Cameron DL; Stem Cell Program, Institute for Regenerative Cures, and Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, USA., Fink KD; Stem Cell Program, Institute for Regenerative Cures, and Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, USA., Beitnere U; MIND Institute, Genome Center, and Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA., O'Geen H; MIND Institute, Genome Center, and Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA., Anderson AE; Department of Pediatrics and Neurology, Baylor College of Medicine, Houston, TX, USA., Dindot SV; Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA., Nash KR; Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA., Weeber EJ; Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA., Wöhr M; Behavioral Neuroscience, Experimental and Biological Psychology, Philipps-University of Marburg, Marburg, Germany., Ellegood J; Mouse Imaging Centre, Toronto Centre for Phenogenomics, The Hospital for Sick Children, Toronto, ON, Canada., Segal DJ; MIND Institute, Genome Center, and Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA., Silverman JL; MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sacramento, CA, USA. jsilverman@ucdavis.edu.
Jazyk: angličtina
Zdroj: Translational psychiatry [Transl Psychiatry] 2020 Jan 27; Vol. 10 (1), pp. 39. Date of Electronic Publication: 2020 Jan 27.
DOI: 10.1038/s41398-020-0720-2
Abstrakt: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3a m-/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3a m+/p- paternal transmission cohort. We also discovered Ube3a m-/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3a m-/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3a m+/p- did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS.
Databáze: MEDLINE